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Ketamine, a pediatric anesthetic, is widely used in clinical practice. There was growing evidence showing that ketamine can promote neuronal death in developing brains of both humans and animals. In this study, we used in vivo neonatal and juvenile mouse models to induce ketamine-related neurotoxicity in the hippocampus. Active caspase-3 and -9 proteins, which are responsible for the release of cytochrome C, and the mitochondrial translocation of p53, which is associated with mitochondrial apoptosis, were found to be significantly up-regulated in the ketamine-induced hippocampal neurotoxicity. Furthermore, we demonstrated that the levels of pyroptosis-related proteins, including caspase-1 and -11, NOD-like receptor family, pyrin domain containing 3 (NLRP3), and IL-1β and IL-18, significantly increased after multiple doses of ketamine administration. We speculated that ketamine triggered the formation of NLRP3 and caspase-1 complex and its translocation to the mitochondria. In consistent with this, ketamine treatment was found to induce pyroptosis in mouse primary hippocampal neurons, which was characterized by increased pore formation and elevated lactate dehydrogenase release in mitochondria. Silencing caspase-1 with lentivirus-mediated short hairpin RNA (shRNA) significantly decreased the levels of not only pyroptosis-related proteins but also mitochondrial apoptosis-associated proteins in mouse primary hippocampal neurons. We conclude that caspase-1-dependent pyroptosis is an important event which may be an essential pathway involved in the mitochondria-associated apoptosis in ketamine-induced hippocampal neurotoxicity.Ketamine, a widely used anesthetic, can cause neuronal death in developing brains.Apoptosis has been a focus in studying ketamine-induced neurotoxicity.We demonstrated a role of pyroptosis in ketamine-induced hippocampal neurotoxicity.Hippocampal apoptosis by ketamine was via pyroptotic NLRP3-caspase-1 complex.Cross talk between pyroptosis and apoptosis may lead to anesthetic neurotoxicity.